Myasthenia gravis (MG) is an autoimmune disorder characterized by muscle weakness caused by autoantibodies, mainly targeting the muscle acetylcholine receptor (AChR) and the muscle specific kinase (MuSK). These antibodies are produced by short-lived plasmablasts and long-lived plasma cells. To date, no MG treatment specifically targets either of these cells. Ixazomib is a proteasome inhibitor used successfully to treat multiple myeloma, a cancer of malignant plasma cells. We propose the IxMG trial to evaluate whether orally administered ixazomib will be safe and have biological and clinical signals of efficacy for patients with treatment-resistant AChR or MuSK MG, which comprise upwards of 30% of the MG population. Patients will be treated with 3 cycles of ixazomib (weekly infusions every week for 3 weeks) during a period of 3 months followed by 3 month follow-up. Clinical and biological monitoring will be performed at time of each treatment and then every 4 weeks. The trial will assess the safety, tolerability, and activity of ixazomib as a therapy for treatment-resistant patients with generalized myasthenia gravis and detailed autoantibody analysis, lymphocyte characterization, and antibody repertoire evaluation. A no-go decision for a Phase 2 assessment will be made for excess adverse effects or lack of target engagement, while a decision to proceed will be made based on safety and confirmation of biological target engagement.